Over the past year the Medical Breast Cancer Section has continued research into four main areas in breast cancer clinical treatment: 1) Dose Intensive Induction Chemotherapy; 2) New Drug Development; 3) Targeted Therapies; and 4) Overcoming Multidrug Resistance. In addition, we have begun work on a major new initiative, the treatment of high risk proliferative breast disease and the identification of intermediate biomarkers of breast cancer development and progression. We have recently completed accrual to a dose intensity clinical trial of FLAC chemotherapy plus IL-3 and GM-CSF for patients with newly diagnosed metastatic breast cancer. In addition, we have treated five patients with high dose ICE chemotherapy and autologous stem cells that have been marked with the neomycin resistance gene. We have nearly finished accrual to a Phase I study of taxol and high dose cyclophosphamide with G-CSF in patients with metastatic breast cancer. This study has emphasized breast cancer tissue acquisition for immunohistochemical analysis of P-gp expression. We have also finished the analysis of our Phase I study of taxol and doxorubicin and G-CSF in patients with previously untreated metastatic breast cancer. Another new drug under study is topotecan, a promising new topoisomerase I inhibitor which we are combining with doxorubicin in an ongoing Phase l study. We have completed our Phase I study of a targeted therapy, the murine monoclonal antibody CC-49 labelled with the new beta emitter, Lutetium-l77. This study represents the first human trial of this novel radioisotope. Another Phase II trial combining tamoxifen with the synthetic retinoid, 4-HPR, is currently ongoing with a major emphasis on studying the upregulation of TGF-beta expression in tumor and normal tissue. Our Phase I study of taxol plus R-verapamil is nearly finished accrual and represents the first study of this novel P-gp blocker in breast cancer patients. Our primary new initiative over the past year has been to develop strategies to develop intermediate molecular biomarkers for breast cancer prevention using the contralateral breasts of breast cancer patients as well as preinvasive proliferative lesions in high risk patients as targets. In the next year we will expand our clinical studies into the treatment of these early breast cancer lesions.